The ACE inhibitors appear to be an attractive choice for managing hypertension and congestive heart failure at all stages.
Cough: mean 15%.
- post-marketing surveillance: 1 - 3%.
- uncontrolled retrospective studies: 6 - 15%.
- controlled studies: 20%.
Rash: 1.3 to 6%.
Angioedema 1/1000 to 7/1000.
Dyspnea and wheezing: ten times less frequent than cough in reports of adverse respiratory reaction.
Women (cough), non smokers (cough).
Idiopathic angioedema (angioedema).
Black Americans, Hong-Kong Chinese (cough).
Asthma is not a risk factor for cough.
- nasal congestion, post-nasal drip, sinusitis
- hypersensitivity pneumonitis
- cough: non productive, dry, tickling. Worse in supine posi tion and at night. Pre-existing cough may be exacerbated. Average time of onset: one week; for as long as the drug is taken; disappearing on average 3-6 days after drug withdrawal.
Rash: maculopapular eruption predominantly occurring on the arms and upper torso, accompanied by pruritus. Usually occurring within the first four weeks of therapy, but more often within the first few days; often transitory, lasting for only a few hours or days and rarely a cause of discontinuation of treatment.
Higher incidence with captopril is related to excessively high doses (600 to 1200 mg/ day) in the first studies.
The rash is sometimes specific to a particular ACE inhibitor.
Angioedema: evolving face, lips, tongue. May be associated with respiratory distress. Often after first dose or within the first few days of treatment. Enalapril: 1/1000 during the first week.
Cutaneous testing (anaphylactic or cutaneous reactions)
Intradermal: 0.05 ml of pure captopril: 0.1/1/10 mg/ ml. Check results after 15 minutes. Positive in 60% of patients with cutaneous manifestations.
Patch tests: pure captopril in vaseline 0.1%; 1 and 10% applied to the patient’s back. Check results after 48 and 72 hours. Positive in 30% of patients with cutaneous manifestations.
Skin biopsy: vasculitis with leukocyte infiltration in patients with cutaneous lesions.
Respiratory function tests: bronchial hyperresponsiveness to histamine or metacholine is sometimes found in patients who develop cough with ACE inhibitors.
Captopril increases plasma levels of prostaglandins. PGE directly stimulates unmyelinated afferent vagal C fibers, the initial chemical mediator of the cough reflex in the lung.
Accumulation of bradykinin which stimulates the release of tachykinins including substance P and neurokinin A.
Tachykinin stimulates the C fibers whose activation causes cough.
Thromboxane A2 is implicated in ACE induced cough.
The mechanism of ACE inhibitor-induced coughing may involve substance P mediated airway priming but the final triggering of the ACE inhibitor-induced cough is unlikely to be due to this peptide.
Substance P is metabolized by ACE in tissues, and ACE inhibitors have previously been shown to decrease its metabolism. Substance P is important in neurogenic inflammation and has a functional relationship via C fibers with mast cells in various tissues, including lung and skin.
Pulmonary accumulation of bradykinin may be a mediator of ACE inhibitor-induced coughing.
Bradykinin is known to activate afferent sensory C fibers via type J receptors which cause coughing. Conversely bradykinin could increase the formation of prostaglandins and leukotrienes.
Inhibition of ACE and/ or related enzymes in the kinine-kallikrein system blocks bradykinin metabolism. In addition, a decrease in bradykinin degradation increases the synthesis of bradykinin and/ or related kinines.
Use another antihypertensive agent (especially if skin-tests are positive: high predictive value) lozartan (angiotensine 2 antagonist) which does not induce cough, but a few cases of angioedema.
Sodium cromoglycate reduces cough scores of 50% by its inhibitor effect on the tachykinin-induced activation of C fibers.
Other drugs are now available: ozagrel (thromboxane A2 synthetase inhibitor), which is effective in the treatment of cough induced by ACE inhibitors.